Oxytocin (OT) plays a role in mammalian social behavior in both model animals and humans. The ability of OT to broadly enhance social cognition makes it a viable candidate for improving social function in psychiatric disorders characterized by social deficits, including Autism Spectrum Disorder. Indeed, intranasal OT has been shown to enhance some facets of social cognition in both healthy and patient populations. Unfortunately, the extent to which intranasal OT penetrates the blood-brain barrier to broadly activate central OT receptors is likely a limiting factor in the efficacy of this therapeutic approach. Melanocortin agonists are proposed as an alternative approach to stimulate central release of OT to enhance social cognition. Melanocortin agonists, acting at the brain-specific melanocortin 4 receptor (MC4R), have been previously shown to stimulate OT release in vitro. The socially monogamous prairie vole (Microtus ochrogaster) is a well-known model for the study of social cognition and social attachment. Formation of a partner preference in the prairie vole is a complex social cognitive process involving social information processing and social reinforcement that is facilitated by OT. We have recently shown that peripheral administration of Melanotan II (MTII), a compound with high selectivity for activating MC4R, enhances partner preference formation in male and female prairie voles. What remains unknown is the precise central mechanism by which MTII enhances partner preference formation, a knowledge gap that prevents accurate assessment of the potential clinical applicability of this approach. The overarching hypothesis of this proposal is that activation of MC4Rs located in the primary source of forebrain OT, the paraventricular nucleus of the hypothalamus, stimulates the OT system to enhance social cognition in the prairie vole. In Aim 1, we will determine whether MTII acts centrally at MC4R to facilitate partner preference formation using pharmacological manipulations combined with behavioral assessments. In Aim 2, we will determine the role of MC4R activation in the paraventricular nucleus of the hypothalamus, and the specific contribution of the OT system, in the behavioral effects of MTII. Aim 2 will use both pharmacological and molecular genetic manipulations in combination with behavioral assessment. The proposed experiments will advance our knowledge of functional social cognition as well as facilitate a greater understanding of how the OT system can potentially be manipulated therapeutically. This is a unique route of investigation in the search for novel treatments of social deficits in human psychiatric disorders.